The receptor for the human immunodeficiency virus (HIV) has been determined to be the T cell accessory protein CD4. Very recently, results from several laboratories have suggested that the blocking of the viral envelope, gp120-CD4 interaction can prevent infection. Thus, agents that are capable of blocking the gp120-CD4 interaction can potentially be useful as therapeutic targets. However, before rational design of such agents can proceed, one must understand the functional interactions between CD4 and this natural ligands, possible the HLA class II gene product and/or the T cell antigen receptor. Furthermore, although the mechanism by which HIV "kill" T cells is not known, it has been suggested that the interaction of gp120 with CD4 is deleterious to the T lymphocytes. Thus, it is possible that the CD4 molecule may be involved in triggering some cellular processes leading to abnormal physiological changes. This grant is aimed at understanding the functional interactions with the CD4 molecule. In specifics, the objectives are: 1) To understand the functional interactions of the HIV receptor CD4 with its natural ligands and the HIV viral envelope. 2) To identify cellular proteins that may associate with CD4 or participate in the activation of the T lymphocytes through the CD4 receptor. 3) To design or search for potential therapeutic targets aimed at arresting or intervening with abnormal processes elicited by HIV infection.